Currently ductal carcinoma in situ (DCIS) accounts for 20-30% of newly diagnosed breast cancers in screened populations. Because of the inability to stratify the DCIS populations at high risk for recurrence and disease progression, many women are currently over-treated and approximately 10-15% patients have disease recurrence despite surgical and adjuvant interventions. Preliminary and published data indicate that a large fraction of DCIS lesions exhibits alterations in the ErbB2 and RB-pathways. However there are no studies investigating effects of both pathways abnormalities in the same DCIS lesion. In this application we using functional studies, will: 1. Define role of RB pathway in progression of ErbB2 overexpressing DCIS and 2. Determine how RB and ErbB2 status impacts response to radiation therapy. PUBLIC HEALTH RELEVANCE: By improving our understating of mechanism driving progression of DCIS to invasive breast cancer the proposed studies will allow for better prognostic stratification of DCIS patients. Additionally we will investigate approaches to treat DCIS rationally based on knowledge of RB and ErbB2 pathways.